Synthesis of (−)-Tetracycline

• Published in: Journal of the American Chemical Society 2005-06, Vol.127 (23), p.8292-8293
• Main Authors: Charest, Mark G, Siegel, Dionicio R, Myers, Andrew G
• Format: Article
• Language: English
• Subjects: Anti-Bacterial Agents - chemical synthesis; Antibacterial agents; Antibiotics. Antiinfectious agents. Antiparasitic agents; Benzoic Acid - chemistry; Biological and medical sciences; Chemistry; Exact sciences and technology; Medical sciences; Noncondensed benzenic compounds; Organic chemistry; Pharmacology. Drug treatments; Preparations and properties; Stereoisomerism; Tetracycline - chemical synthesis
• ISSN: 0002-7863; 1520-5126
• DOI: 10.1021/ja052151d

We describe a convergent, enantioselective synthesis of (−)-tetracycline (1) from benzoic acid (17 steps, 1.1% yield). Benzoic acid was transformed into the AB precursor 2 in 10 steps (11% yield), as previously described, and the latter compound was activated toward Diels−Alder cycloaddition by the introduction of an α-phenylthio group (two steps, 66% yield). Heating of the resulting α-(phenylthio)enone (3) with the triethylsilyloxybenzocyclobutene derivative 4 at 85 °C gave the endo-Diels Alder adduct 5 in 64% yield. Deprotection and oxidation of the latter intermediate gave the 2-(phenylthio)-1,3-diketone 7, which was oxidized with m-chloroperoxybenzoic acid in the presence of trifluoroacetic acid. The sulfoxide intermediate(s) formed eliminated upon warming to 35 °C to give the anyhydrotetracycline derivative 8. Intermediate 8 underwent spontaneous autoxidation at 23 °C to form the hydroperoxide keto-9 stereoselectively. Without isolation, hydrogenolysis of 9 in the presence of palladium black gave (−)-tetracycline (42% yield from 7), indistinguishable from an authentic sample.